PROJECT SUMMARY: Cerebrovascular disease is among the most common neurological diseases of aging and is increasing in prevalence with changing demographic trends. The two most common consequences of cerebrovascular disease are cognitive and motor decline, which are major contributors to poor health outcomes and mortality. Identifying associated factors, particularly ones for which treatments are available, is a priority for researchers in aging. Recent data suggest that antiphospholipid antibodies (aPL) increase in aging, and are present in about 35% of persons over the age of 80 years. While aPL increase risk of stroke by about two-fold, their relation to decline in cognitive and motor function, perhaps through an association with both clinical and subclinical cerebrovascular disease, is unclear. The proposed epidemiologic study will take advantage of a cohort of 1,100 community-dwelling women and men who are followed longitudinally with a high follow-up rate, and who come to autopsy with a high autopsy rate (R01AG17917), to test the hypotheses that aPL are related to cognitive and motor decline. The study will also examine the relation of aPL to cerebrovascular disease, including subclinical cerebrovascular disease assessed by complementary ante-mortem neuroimaging and postmortem neuropathology, and the extent to which aPL are related to cognitive and motor impairment after controlling for this disease. This would suggest the existence of neurobiologic mechanisms other than cerebrovascular disease linking aPL and cognitive and motor dysfunction. Finally, because factors with effects other than vascular may influence relations, the study will examine the role of makers of inflammation and altered blood-brain barrier permeability. The proposed study, relating aPL and other markers to cognitive and motor decline, and cerebrovascular disease in older, community-dwelling persons, will provide new knowledge regarding the role of aPL in common neurological conditions of aging. Because aPL are common vascular factors for which treatments are available, this study will provide new data which has the potential to improve public health by shifting current clinical practice paradigms and reducing the burden of neurological disease in aging.